1. Field of the Invention
This invention relates to novel indolo[3,2-c]quinoline compounds, which have been proven to inhibit both growth of a variety of cancer cells and activity of telomerase, a common target for treating cancer. This invention also relates to the applications of said compounds in the manufacture of pharmaceutical compositions.
2. Description of the Related Art
Ever since isocryptolepine, one of the indolo[3,2-c]quinoline-type alkaloids, was isolated from Cryptoleptis sanguinolenta (a plant used in traditional medicine against malaria), several indolo[3,2-c]quinoline compounds have been synthesized and extensively studied as potential antiplasmodial agents. See, e.g., Timari, G. et al., Synlett. 1997, 1067; Devaraj, R. et al., Bioorg. Med. Chem. Lett. 1997, 7, 369; Xiao, Z. et al., Bioorg. Med. Chem. 2001, 11, 2875-2878; Kumar, R. N. et al., Tetrahedron Lett. 2002, 43, 3327; Mulwad, V. V. et al., Indian J. Chem. Section B, 2003, 42B, 1937; and Miert, S. V. et al., J. Nat. Prod. 2005, 68, 674-677. Some indolo[3,2-c]quinoline compounds were prepared and evaluated for anticancer effects. See, e.g., Chen, Y. L. et al., Bioorg. Med. Chem. 2002, 10, 2705; Lin, Y. H. et al., Drug Dev. Res. 2006, 67, 743; and Hu, X. W. et al., Cell Biol. Toxicol. 2006, 22, 417. Indolo[3,2-c]quinoline compounds have a tetracyclic heterocycle that can intercalate into the double helix of DNA to block DNA replication or transcription, resulting in inhibition of tumor cell growth. See, e.g., Molina, A, et al., J. Org. Chem. 1996, 61, 5587.
EP 0226508 A1 discloses indolo[3,2-c]quinoline derivatives of the following formula (I):
in which n denotes an integer from 2 to 4, R1 denotes hydrogen or a lower alkyl group, R2 and R3 denote hydrogen or a lower alkyl group, or else R2 and R3 form together and with the nitrogen atom to which they are attached a saturated heterocyclic ring which may contain a second heteroatom such as oxygen, sulfur or nitrogen, and R4 denotes a hydroxyl group or a lower alkoxy group;and their addition salts with pharmaceutically acceptable inorganic or organic acids and the tautomeric forms when they exist.
In previous studies, the applicants synthesized several N-substituted 11H-indolo[3,2-c]quinolin-6-amines and evaluated the same in vitro against a full panel of 60 human tumor cell lines derived from nine cancer cell types at the US National Cancer Institute (NCI), amongst which N′-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethyl-ethane-1,2-diamine (IQDMA) was observed to exhibit potential anticancer effects against human leukemia HL-60 cells with 50% cell growth inhibition (GI50) of 1.98 μM (Yeh-Long Chen et al. (2002), Bioorganic & Medicinal Chemistry, 10:2705-2712; Yi-Hsiung Lin et al. (2006), Drug development research, 67:743-751; and Xiu-Wei Hu et al. (2006), Cell Biol. Toxicol. 22:414-427).

In spite of the aforesaid, for pharmachemists and manufacturers in the Pharmaceutical Industry, there still exists a need to develop new compounds that can be easily prepared and that are suitable for use in the treatment of a variety of cancers and tumors.